What does this research mean for the field?

Tyrosine kinase inhibitors alter skeletal muscle energy metabolism, and lower muscle oxidative capacity is associated with the severity of TKI-induced muscle complaints in patients with chronic myeloid leukemia. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to understand how tyrosine kinase inhibitors affect skeletal muscle metabolism and relate to muscle complaints in CML patients.

June 8, 2026Open Access

Effects of tyrosine kinase inhibitors on skeletal muscle metabolism: a link with muscle complaints

LJLando JanssenRadboud University Nijmegen CHCharlotte A. HoogstratenRadboud University Nijmegen NANeeltje A. E. AllardRadboud University Nijmegen

Key Points

This research aims to understand how tyrosine kinase inhibitors affect skeletal muscle metabolism and relate to muscle complaints in CML patients.
Comparative analysis of muscle biopsies from 20 CML patients and 10 healthy controls.
In vitro studies using C2C12 myotubes to assess TKI effects on muscle metabolism.
Measurement of mitochondrial complex activities and energy metabolism shifts in response to TKIs.
TKI muscle concentrations in CML patients correspond to cytotoxic levels observed in C2C12 myotubes.
CML patients without muscle complaints exhibited higher oxidative capacity and mitochondrial activity.
Acute TKI exposure in C2C12 myotubes shifted energy metabolism from glycolysis to oxidative phosphorylation.

Abstract

Chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKIs) often report muscle complaints (MC). Strategies to prevent or attenuate these muscle complaints remain enigmatic as the underlying mechanism is unclear, although a central role for mitochondria is proposed. We investigated the effects of TKIs on cellular metabolism in muscle biopsies of CML patients (n = 20), compared with healthy controls (n = 10) and whether these changes may be linked to muscle complaints. C2C12 myotubes were used to further explore the effects of TKIs on muscle metabolism in vitro. We found that TKI muscle concentrations in CML patients aligned with the concentrations at which cytotoxicity could be observed in C2C12 myotubes, and that muscle to plasma ratios tended to correlate with the degree of MC in CML patients. In C2C12 myotubes, acute TKI incubation of C2C12 myotubes resulted in alterations in energy metabolism, showing a shift from glycolysis to oxidative phosphorylation. CML patients without MC showed higher oxidative capacity, characterized by higher mitochondrial complex activities in skeletal muscle and occurrence of the first ventilatory threshold at a higher percentage of peak oxygen uptake during maximal exercise compared to patients with MC. Taken together, these observations raise the possibility that TKIs may affect cellular energy metabolism and may contribute to muscle complaints.Trial registration The Netherlands Trial Registry identifier NTR6373.

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